Since insulin action in vivo in man is correlated with the density of the capillary supply to skeletal muscle, we hypothesize that since the unfenestrated capillaries of skeletal muscle are relatively impermeable to insulin that the increased insulin resistance in those with low capillary density might be due to altered kinetics of insulin penetration to its sites of action in the muscle. A method was developed to directly collect lymph from a peripheral lymphatic vessel in sufficient amounts to measure insulin, and glucose during changes in arterial insulin concentrations. Insulin concentrations in limb lymph were found to be considerably lower than that in plasma and in contrast to plasma insulin concentrations, lymph concentrations were highly correlated with glucose uptake rates in each individual. In insulin resistant subjects, the slope of the glucose uptake, lymph insulin relationship was much steeper than in lean subjects. Therefore, interstitial insulin concentrations determine insulin action in an individual but the between individual variation in insulin sensitivity is more determined by distal pathways that lead to insulin mediated glucose uptake.